HITHOC & the guidelines for management of malignant pleural mesothelioma: Why inclusion matters

Dr. Marcelo Migliore, Dr. Stefan Hoffman and several other thoracic surgeons who spearhead large HITHOC (Hyperthermic intrathoracic chemotherapy) research programs have just authored an editorial for the latest December 2020 issue of the Annals of Translational Medicine.

In this thoughtful article, the authors comment on the absence of any mention or consideration of HITHOC for the treatment of malignant Pleural Mesothelioma (MPM) despite multiple studies showing as survival advantage for patients receiving HITHOC*.

You can read the editorial here.

Migliore et al. point out a couple of things in their arguments for inclusion:

Stating (paraphrasing for brevity) that given the current level of evidence for most of the existing treatments of MPM are rated as weak, it is difficult to understand why HITHOC remains excluded from consideration. This gives the erroneous impression that HITHOC is a new, untried/ untested experimental treatment with little to no evidentiary support. This is false. Even a cursory overview of the data shows this is clearly not the case.

Why is this important, you ask??

Doctors, (at least credible ones), don’t offer or refer patients for treatments that fall outside the approved guidelines. Referring patients for treatments outside of the approved guidelines is considered charlatanism at best, and medical malpractice at worst. It’s akin to giving your patient megavitamin supplements and sending them to a Laetrile clinic, instead of an oncologist. This is particularly unethical when dealing with cancer patients because the direness of their prognosis can make them susceptible to the worst medical scams in our society. But this also means that doctors are hesitant to send their patients for legitimate treatments such as HITHOC because it isn’t “recommended.”

-And.. and it’s not a small AND.. the current “recommended” treatments don’t have strong evidence supporting their use (or a lot of good outcomes.)

Now as the editor of thoracics.org, I am going to take argument this a little bit farther than the authors did in their article.

Migliore and his fellow authors are European.. So they and the majority of their patients don’t fall victim to the “American medical insurance conundrum”, where Americans pay enormous sums of money to insurance carriers who then turn around and deny payment for necessary medical treatments. But, most of my patients are American, so inclusion matters a lot to me, because inclusion or specifically, the lack of inclusion drives a lot of insurance payment decisions.

One of the ways insurance companies save money is by denying payment for any treatment that is considered experimental. (What an insurance company deems experimental can also be controversial but that’s another conversation). Whether that so-called experimental treatment has a high probability of saving or prolonging your life is not important to the insurance company. (In fact, for decades after bone marrow transplant was shown to be a very effective form of treatment for several types of cancers, insurance companies continued to deny coverage – because bone marrow transplant is expensive.)

In fact, this scenario was the basis for a very popular 1997 movie based on the John Grisham novel, “The Rainmaker.

(In the movie, Danny Davito and Matt Damon are in my hometown of Memphis, fighting for a client whose insurance has denied him a life-saving bone marrow transplant. )

As mentioned by the authors in the editorial, the omission of HITHOC from the guidelines suggests that it’s experimental. But as we’ve shown in multiple reviews of the data surrounding HITHOC, it’s been around for over 20 years and has a lot of data to support it’s use.

Even when a treatment isn’t deemed “experimental”, insurance companies don’t have to cover it. They routinely deny payments for treatments that are not part of standard treatment guidelines, so Inclusion in clinical guidelines is the first step to having the treatment included as part of Medical coverage.

In the case of HITHOC, inclusion in the clinical guidelines is critical. Patients with malignant pleural mesothelioma (and other cancers that are treated with HITHOC), don’t have a lot of time – and frankly, without HITHOC, their prognosis, and estimated survival time are both measured in single digits.

Without inclusion – patients never make it from their doctor’s office to the research program. Even if they somehow did find their way there (thru google, word-of-mouth or other means), most patients don’t have the means to pay for it, if insurance won’t help. (Even European programs, which are much more affordable than American programs, HITHOC can cost from 40,000 to 80,000 dollars. In the USA, the cost has been quoted as around a quarter of a million dollars.) So, inclusion matters.

For more information about any of the things we’ve talked about above: (about criteria for recommendations, current malignant pleural mesothelioma guidelines and all things HITHOC)

If you’ve never read a paper reviewing the guidelines for treatment of a medical condition, then you should know a couple of things first.

  • in these papers, multiple strategies or treatment options are listed
  • each of these treatments is then given a letter grade of A, B, or C based on the amount of scientific evidence that it works. (For more about the levels of evidence, see this article on the evidence pyramid).
  • A treatment with a high level of evidence (lots of scientific data, meta-analyses, double-blinded studies with large numbers of participants, etc.) would be ranked as 1A.
  • If we had another treatment, that seemed really effective, but maybe the evidence wasn’t quite as strong for that exact circumstance, it might be listed as 1B. As the supporting evidence for the treatments is reduced, treatments are graded as B, C and X. Level B recommendations are still things we still might consider using for patients, but less so for level C. Level X means that the treatment may actually cause harm. (Level X is often applied to treatments that were used historically, but are later found not to work. This happens quite a bit if you look at treatments used in the 1960’s versus now.)

So the authors are asking for HITHOC be mentioned in these guidelines, to be then ranked based on evidence. Since the evidence is graded, as we explained above, the authors aren’t asking for HITHOC to replace other treatments. They are merely asking for it to be listed as an option.

What are the current guidelines for treatment of MPM?

The current European guidelines for treatment of MPM are here. (In this guideline, they dispense with the standard grades of A, B, C and basically skip to palliative treatments in most cases. For example, they “recommend” talc pleurodesis as the first line surgical treatment – which as readers know, is a palliative treatment based on symptom management only.

The American recommendations also eshew the standard grading nomenclature, but A, B, C are merely substituted with srong, moderate and weak.

What about HITHOC? What is HITHOC?

*Many of those studies have been reviewed here at Thoracics.org: we have a whole section dedicated to cytoreductive surgery and hyperthermic intrathoracic chemotherapy (HITHOC).

HITHOC review of the literature (2018)

Mesothelioma, Hope and HITHOC

Is there hope? Thoracics.org discusses hope and mesothelioma along with the most recently published work in the area of cytoreductive surgery and intrathoracic chemotherapy (HITHOC).

Is there hope?

In a recent article in Future Oncology, Dr. Maat and his colleagues explore the question of whether hope exists for patients with malignant pleural mesothelioma (MPM).   The authors acknowledge the difficulties for patients and providers alike in maintaining hope when the odds are against it.  Dr. Maat also discusses the differences between offering false hope and belief in the possibilities of emerging therapies.


“Dismal” prognosis of malignant mesothelioma

This brings to the forefront one of the biggest failures in thoracic surgery and oncology; malignant mesothelioma.  While great strides have been made in the last fifty years in the treatment of many other cancers, malignant mesothelioma continues to carry a dismal prognosis with a lifespan measured in months.  Not only that, but even the great “wins” in this area, like pleural decortication, are often only viewed as such when measured against palliative treatment (Zahid, Sharif, Routledge & Scarci, 2011).

This is one of the reasons Thoracics. org has taken such an interest in emerging therapies and research in areas such as HITHOC, and will continue to do so.  Sometimes even the most promising data takes a dead-end, like in the case of Dr. Isik in Ganziantep, Turkey, where HITHOC and mesothelioma research have been forced to take a backseat to ISIS and the Syrian refugee crisis.  This along with financial limitations (unfunded research) have threatened a promising program.

Dr. A. Feridun Işık and his team perform cytoreductive surgery and the HITHOC (HIPEC) procedure
Dr. A. Feridun Işık and his team perform cytoreductive surgery and the HITHOC (HIPEC) procedure (in 2014)

In situations like Dr. Isik’s, it is easy for readers and other researchers themselves to lose hope.  If programs showing favorable results like Dr. Isik’s can not survive, how can we expect support for additional research in this area?  But just as Dr. Maat advocates for hope among patients, and providers, we here at Thoracics.org continue to advocate for a hopeful future in the area of HITHOC; not just for malignant pleural mesothelioma, but for a whole spectrum of cancers that remain frustratingly difficult to treat.

Migliore et al. 

As such, Thoracics.org would like to highlight some of the most recent HITHOC publications.  Two of these studies are from Dr. Migliore and his colleagues at Catania, Italy.  The first paper, describes their preliminary experiences with eight patients (6 patients with MPM and 2 patients with lung cancer).  The authors discuss inclusion criteria, methodology and surgical technique (uniportal VATS/ and mini-thoracotomes) including one hour of chemoperfusion with cisplatin at 42.5 degrees centigrade.  Interestingly, in this tiny subset of patients, the surgeons included one patient who underwent diaphragmatic resection, which is usually considered a contraindication to the procedure according to most researchers*.  When we review the post-operative survival of these patients in this and the subsequent publication, it is worth asking about the specific survival time of the patient with diaphragmatic resection, and whether disease recurred in this specific patient.

The authors also included 2 patients with adenocarcinoma of the lung with pleural metastases in their priliminary series.  One of these patients had previously undergone talc pleurodesis.

Consistent with other recently published reports, mortality for this limited study was 0% (or much lower than what was previously reported during the “first generation” of cytoreductive surgery with hyperthermic chemotherapy in the early 2000’s).  Additional post-operative complications included 2 cases of post-operative nausea/ vomiting and one patient with acute kidney injury (post-operative creatinine 2.0).

The second publication by Migliore et al., also in Future Oncology is an expanded discussion of the six malignant pleural mesothelioma patients with better survival outcomes as 4 patients survival extended past the time of publication (one death at 6 months post-operative, one death at 24 months).

Anesthesia and HITHOC 

While this article dates back to mid 2014, Kerscher et al. is one of the only authors to investigate and describe the unique challenges for anesthesiologists managing these patients during the intra-operative and post-operative period.  Kerschner and colleagues report on their experiences with 20 patients undergoing cytoreductive surgery and HITHOC at the University Medical Center in Regensberg, Germany from 2008 to 2013.  In addition to describing the intra-operative anesthetic and post-operative analgesic techniques used as their institution, Kerscher et. al also delve into the specific management strategies related to the use of HITHOC, such as the addition of ventilatory peep during the cycling of hyperthermic chemotherapy to increase the amount of lung surface area exposed to the chemotherapeutic agents (cisplatin in this study).

Recommended reading

Their discussion of the management of intra-operative challenges caused by the infusion of chemotherapy such as low cardiac output, hypotension, pulmonary edema and coagulopathies along with an in-depth look at hemodynamics, volume resuscitation, challenges in ventilation and normothermia make this paper recommended reading for any surgeons or institutions interested in piloting their own HITHOC program.  This article also serves as a reminder that while many small studies report minimal complications, there can and are serious and potentially fatal intra-operative complications in patients undergoing HITHOC.

Like Dr. Hung and Dr. Chen, this paper serves an important reminder that all advancements and discoveries in thoracic surgery require a cohesive, teamwork approach.

*Most surgeons who perform HITHOC / HIPEC exclude patients with diaphragmatic involvement because this is believed to make it impossible to prevent widespread dissemination of disease – since the diaphragm is the physical, tissue barrier that separates the chest cavity from the abdomen.


Maat, A., Cornelissen, R., Bogers, J. & Takkenberg, J. (2015). Is the patient with mesothelioma without hope?  Future Oncol., 2015, 11 (24s), 11-14.

Migliore M, Calvo D, Criscione A, Viola C, Privitera G, Spatola C, Parra HS, Palmucci S, Ciancio N, Caltabiano R, Di Maria G. (2015).  Cytoreductive surgery and hyperthermic intrapleural chemotherapy for malignant pleural diseases: preliminary experience.  Future Oncol. 2015;11(2 Suppl):47-52. doi: 10.2217/fon.14.256.

Migliore M, Calvo D, Criscione A, Palmucci S, Fuccio Sanzà G, Caltabiano R, Spatola C, Privitera G, Aiello MM, Parra HS, Ciancio N, Di Maria G. (2015).   Pleurectomy/decortication and hyperthermic intrapleural chemotherapy for malignant pleural mesothelioma: initial experience.  Future Oncol. 2015 Nov;11(24 Suppl):19-22. doi: 10.2217/fon.15.286.

Kerscher C, Ried M, Hofmann HS, Graf BM, Zausig YA. (2014).  Anaesthetic management of cytoreductive surgery followed by hyperthermic intrathoracic chemotherapy perfusion.  J Cardiothorac Surg. 2014 Jul 25;9:125. doi: 10.1186/1749-8090-9-125.  An excellent overview of intra-operative management considerations for patients undergoing HITHOC procedures.  Recommended reading.